Hepatitis C virus (HCV) infection is difficult to treat as it can quickly mutate and escape the natural immune response. The HCV genome, containing a single polyprotein of about 3000 amino acids, includes a nucleocapsid protein, envelope proteins (E1 and E2), and several non-structural proteins (p7, NS2, NS3, NS4A, NS5A, and NS5B). Among these proteins, the NS3 protein possesses serine protease activity and is considered essential for viral replication and infectivity. HCV NS3 protease, which facilitates proteolysis at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, NS5A/NS5B junctions, is responsible for generating four viral proteins during viral replication. Consequently, the HCV NS3 protease is an attractive target in treating HCV infection.
Certain macrocyclic compounds have demonstrated a potential for inhibiting NS3/4A proteases activity, decreasing HCV RNA levels, and inhibiting HCV protease mutants that are resistant to various HCV inhibitors. See Liu et al., U.S. Pat. No. 8,389,560. On the other hand, these compounds exhibit poor pharmacological properties, e.g., low solubility and low bioavailability, thereby restricting their use as effective therapeutics for treating HCV infection.
There is a need to develop new formulations that contain these macrocyclic compounds yet do not have the above-described drawbacks.